Phenoxypropionic acid derivatives

ABSTRACT

Phenoxypropionic acid derivatives of the formula ##SPC1## 
     Wherein Q is H or a halogen atom, R is H or CH 3 , Z is --OH, --O-alkyl of 1-4 carbon atoms, 1-methyl-4-piperidyloxy, or --NHCH 2  CH 2  OH, and the physiologically acceptable salts thereof; possess cholesterol and triglyceride blood-level lowering activity and can be prepared, e.g., by reaction of a phenol of the formula ##SPC2## 
     With a compound of the formula X--CR(CH 3 )--CO--Z wherein X is Cl, Br, I, or a free or esterified OH-group, and Q, R and Z have the values given above.

BACKGROUND OF THE INVENTION

This invention relates to novel phenoxypropionic acid derivatives.

U.S. Pat. No. 3,804,839 discloses 2-p-(heterocyclic ring)- andp-(2-indanyl)-phenoxy-2-methyl-propionic acids and alkyl esters thereofhaving cholesterol and triglyceride blood level lowering activity.Nakamura et al., Chem. Abstracts 75, 151545 (1971), disclosescorresponding compounds wherein the p-substituent on the phenyl ring iscycloalkenyl, benzothiazolyl or benzoxazolyl. Dujovne et al., Chem.Abstracts, 74, 75049, discloses corresponding compounds wherein thep-substituent is tetrahydronaphthyl (nafenopin) or chloro (clofibrate),as having cholesterol and triglyceride blood level lowering activity.The p-substituent on the phenoxy substituent of the compounds of thisinvention is phenoxymethyl or halophenoxymethyl.

SUMMARY OF THE INVENTION

The compounds of this invention are those of the general Formula 1##SPC3##

Wherein Q is H, F, Cl, Br, or I; R is H or CH₃ ; Z is --OH, --OR₁, or--NHCH₂ CH₂ OH; and R₁ is alkyl of 1-4 carbon atoms or1-methyl-4-piperidyl, and the physiologically acceptable salts thereofwith acids and bases.

DETAILED DISCUSSION

Compounds of Formula 1 possess, with good compatibility, outstandingcholesterol blood-level-lowering and triglyceride blood-level-loweringactivity, as well as enzyme-inducing effects.

The compounds of Formula 1 and their physiologically acceptable saltsare useful as medicinal agents and also as intermediates for theproduction of other drugs.

Preferred compounds of Formula 1 are those wherein

A. Z is --OH;

b. Z is 1-methyl-4-piperidyloxy;

C. Z is methoxy or ethoxy; and

D. Q is H or Cl, especially those of (a), (b) and (c).

As will be apparent, only those compounds wherein Z is --OH can formpharmaceutically acceptable salts with bases and those wherein Z is1-methyl-4-piperidyl can form pharmaceutically acceptable salts withacids.

In its process aspect, this invention relates to a process for theproduction of compounds of Formula 1 and physiologically acceptablesalts thereof with acids or bases, which comprises:

A. REACTING A PHENOL OF Formula 2 ##SPC4##

Wherein Q has the values given above, with a compound of Formula 3

    X--CR(CH.sub.3)--CO--Z                                     (3)

wherein X is Hal or a free or esterified OH-group, Hal being Cl, Br, orI, and R and Z have the values given above or with a haloform andacetone in the presence of a condensation agent; or

b. reacting a phenol of Formula 4 ##SPC5##

wherein Q has the values given above, with a compound of Formula 5##SPC6##

wherein X, R, and Z have the values given above; or

c. in a compound of Formula 6 ##SPC7##

wherein W is a group convertible into the group --CO--Z and Q, R, and Zhave the values given above, W is converted into the group --CO--Z;optionally thereafter the Z group of a thus-obtained compound of Formula1 is converted into another Z group by treatment with a solvolyzing,thermolyzing, ester-forming, or amidating agents and/or optionally athus-produced compound of Formula 1 wherein Z is OH is converted bytreatment with a base into a physiologically acceptable metal orammonium salt thereof or a compound of Formula 1 wherein Z is1-methyl-4-piperidyloxy is converted with an acid into a physiologicallyacceptable acid addition salt thereof and/or a compound of Formula 1 isliberated from such a salt by treatment with a base or an acid,respectively.

X is preferably Cl or Br, and also especially a reactively esterifiedOH-group, e.g., an alkylsulfonyloxy of especially 1-6 carbon atoms (forexample, methanesulfonyloxy), arylsulfonyloxy of particularly 6-10carbon atoms (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or2-naphthalenesulfonyloxy). X can also be I, OH, or acyloxy, preferablyof 1-7 carbon atoms (e.g., acetoxy or benzoyloxy).

The compounds of Formula 1 can be obtained particularly in accordancewith methods known per se and described in the literature by reactingthe phenols of Formulae 2 and 4, respectively, with compounds 3 and 5,respectively. Compounds of Formulae 3 and 4 are, for the most part,conventional and can be obtained according to known methods. The phenols2 can be produced by reacting p-nitrobenzyl bromide with a phenol 4 toproduce a p-nitrobenzyl-p'-Q-phenyl ether, reduction to the aminocompound, diazotization, and hydrolysis. The compounds of Formula 5 areobtainable, for example by the reaction of p-hydroxybenzyl alcohol witha compound of Formula 3 and, if desired, subsequent conversion of thealcoholic OH-group into another X group, for example, by reaction withan inorganic acid halogenide or by acylation.

A phenol of Formula 2 or 4 can, for example, first be converted into asalt, especially a metallic salt, e.g., an alkali metal salt (Li, Na orK salt). The phenol can be reacted with a reagent forming a metallicsalt, for example, an alkali metal (e.g., Na), an alkali metal hydride,or an alkali metal amide (e.g., LiH or NaH, NaNH₂ or KNH₂), a loweralkali metal alcoholate (e.g., lithium, sodium or potassium methylate,ethylate, or tert.-butylate), an organometallic compound derived from ahydrocarbon (e.g., butyllithium, phenyllithium or phenylsodium), a metalhydroxide, carbonate, or bicarbonate (e.g., of Li, Na, K or Ca). Thephenolate is advantageously prepared in the presence of a solvent orsolvent mixture. Suitable solvents are, for example hydrocarbons (e.g.,hexane, benzene, toluene, or xylene), ethers [e.g., diethyl ether,diisopropyl ether, tetrahydrofuran (THF), dioxane, or diethylene glycoldimethyl ether], amides e.g., dimethylformamide (DMF) orhexamethylphosphoric triamide (HMPA), alcohols (e.g., methanol orethanol), ketones (e.g., acetone or butanone).

A phenol of Formula 2 or 4 or a salt thereof is reacted with a compoundof Formula 3 or 5, preferably in the presence of a diluent, for example,the solvent utilized for the production of the salt, which can, however,be replaced by or diluted by another solvent. The reaction is normallyconducted at temperatures of from -20° to 150°, preferably 20° to 120°.

The metallic salt of a phenol of Formula 2 (or 4) can also be formed insitu, in which case the phenol and compound of Formula 3 and 5,respectively, are reacted with each other in the presence of a base. Aparticularly preferred method resides in refluxing the phenol and acompound of Formula 3 or 5 (X = Cl or Br) together with an alcoholic(e.g., ethanolic) sodium alcoholate solution for several hours.

It is also possible to react the free phenol with a hydroxy derivativeof Formula 3 or 5 (X = OH), preferably in the presence of a condensationagent. Suitable condensation agents are acidic dehydration catalysts,for example, mineral acids, e.g., sulfuric acid or phosphoric acid,p-toluenesulfonyl chloride, arsenic acid, boric acid, NaHSO₄ or KHSO₄,disubstituted carbonic acid esters, e.g., diaryl carbonates (forexample, diphenyl carbonate) or especially dialkyl carbonates (e.g.,dimethyl or diethyl carbonate) or carbodiimides (e.g.,dicyclohexylcarbodiimide). If an acid serves as the condensation agent,the reaction is advantageously effected in an excess of this acidwithout the addition of a further solvent, at temperatures of between 0°and 100°, preferably 50° and 60°. However, it is also possible to adddiluents, e.g., benzene, toluene, or dioxane. When using a carbonate,the reaction is preferably conducted at an elevated temperature,suitably between 100° and 210°, especially between 180° and 200°,wherein a transesterification catalyst can be added, such as sodium orpotassium carbonate or an alcoholate (e.g., sodium methylate).

Compounds of Formula 1 are also obtainable in accordance with methodsknown from the literature from compounds of Formula 6 by converting theW group thereof into the group --CO--Z, usually by solvolysis(preferably hydrolysis), or, for example, by amidation or oxidation. Inparticular, W is CN or CONH₂, but can also be one of the following(wherein R₂ and R₃ each are alkyl of 1-4 carbon atoms, preferably methylor ethyl, and can be identical or different and, collectively, can alsobe tetramethylene or pentamethylene, optionally interrupted by O): CHal₃; COHal; COOA (wherein A is optionally substituted alkyl of up to 18carbon atoms); C(OR₂)₃ ; COOAcyl (wherein Acyl is the acyl radical of acarboxylic acid of up to 18 carbon atoms); CONHR₂ ; CONR₂ R₃ ; CONHOH;C(OH)=NOH; CONHNH₂ ; CON₃ ; C(OR₂)=NH; C(NH₂)=NNH₂ ; C(NHNH₂)= NH; CSOH;COSH; CSOR₂ ; CSNH₂ ; CSNHR₂ ; CSNR₂ R₃ ; CH₂ OH; or CHO. Compounds ofFormula 6 are obtainable, for example, by the reaction of a phenol ofFormula 2 with a compound of the formula X--CR(CH₃)--W or of a phenol ofFormula 4 with a compound otherwise corresponding to Formula 5 buthaving a W group instead of the group --CO--Z.

Hydrolysis of compounds of Formula 6 (W=functionally modifiedCOOH-group) can be effected in an acidic, neutral, or alkaline medium attemperatures of from -20° to 300°, preferably at the boiling point ofthe selected solvent. Examples of suitable acidic catalysts arehydrochloric, sulfuric, phosphoric, or hydrobromic acid; suitable basiccatalysts are, e.g., sodium, potassium, or calcium hydroxide and sodiumor potassium carbonate. As solvents, preferred are water; loweralcohols, e.g., methanol, ethanol; ethers, e.g., THF, dioxane; amides,e.g., DMF; nitriles, e.g., acetonitrile; sulfones, e.g.,tetramethylenesulfone; or mixtures thereof, especially water-containingmixtures. However, the acid derivatives can also be saponified tocarboxylic acids of Formula 1 (Z=OH), for example, in ether or benzenewith the addition of a strong base, e.g., potassium carbonate, or in theabsence of solvent by melting with an alkali, e.g., KOH and/or NaOH oran alkaline earth.

A preferred embodiment of the invention is the hydrolysis of amides ornitriles (6, W = CONH₂ or CN), which can be accomplished in an acidicmedium (for example with acetic acid/HCl) or in an alkaline medium(e.g., with KOH in cyclohexanol).

It is also possible to convert acid halogenides, anhydrides and nitrilesof Formula 6 (W = COHal, COOAcyl, or CN) into esters of Formula 1 (Z =OR₁) in accordance with methods described in the literature by reactionwith an alcohol of the formula R₁ OH, optionally in the presence of anacidic catalyst or base, e.g., NaOH, pyridine, or an alkali metalalcoholate corresponding to the alcohol employed. Preferably, an excessof the respective alcohol is used, and the reaction is carried out attemperatures of from 0° to the boiling temperature.

Esters of Formula 1 (Z = OR₁) can also be obtained by solvolyzingcompounds of Formula 6 wherein W is a thioester, imino ether, oximinoether, hydrazone ether, thioamide, amidine, amidoxime, or amidehydrazone grouping, with a dilute aqueous base or acid, e.g., ammonia,NaOH, KOH, Na₂ CO₃, K₂ CO₃, HCl, H₂ SO₄, with the addition of therespective alcohol of the formula R₁ OH, splitting off hydrogen sulfide,ammonia, amines, hydrazine derivatives, or hydroxylamine. Most of theimino ether hydrochlorides disintegrate in an aqueous solutionimmediately into the esters and ammonium chlorides at room temperature.The solvolysis of some amidoximes or thioamides takes place only attemperatures of up to 100°.

It is also possible to convert compounds of Formula 6, particularly theacid halogenides (W = COHal), into the corresponding ethanolamidesaccording to methods known per se by reaction with ethanolamine.Alcohols and aldehydes of Formula 6 (W = CH₂ OH and/or CHO) can beoxidized according to conventional methods, for example with CrO₃ orKMnO₄, to the carboxylic acids 1 (Z = OH).

If desired, the Z group of a thus-obtained compound of Formula 1 can beconverted into another Z group by treatment with solvolyzing,thermolyzing, ester-forming or amidating agent.

A solvolysis of an ester or amide of Formula 1 (Z = OR₁ or NHCH₂ CH₂ OH)can be accomplished according to the above-indicated conditions,preferably by hydrolysis in an alkaline medium.

The thus-obtained esters of Formula 1 (Z = OR₁, especially Z =O-tert.butyl) can be converted into the corresponding acids of Formula 1(Z = OH), by dry heating to temperatures of between 50° and 350°. Thethermolysis can also be conducted in inert solvents, for example inwater, DMF, dimethyl sulfoxide, cyclohexanol, ethylene glycol, orbenzene, preferably with the addition of a catalytic amount of an acid,e.g., p-toluenesulfonic acid.

Esters of Formula 1 (Z = OR₁) can be prepared according to methods knownin the literature, for example, by reacting an acid of Formula 1 (Z =OH) with the respective alcohol of the formula R₁ OH, preferably in thepresence of an inorganic or organic acid, e.g., HCl, HBr, HI, H₂ SO₄, H₃PO₄, trifluoroacetic acid, benezenesulfonic acid, or p-toluenesulfonicacid, or in the presence of an acidic ion exchanger, together with or inthe absence of an inert solvent, e.g., benzene, toluene, or xylene, attemperatures of from 0° to preferably the boiling temperature of themixture. The alcohol is advantageously used in excess. The reaction canbe carried out in the presence of a water-binding agent, e.g., anhydrousheavy metal salts (for example, CuSO₄ or ZnCl₂) or in the presence of amolecular sieve. It is also possible to remove the water of reactionazeotropically and, in this case, a hydrocarbon (e.g., benzene ortoluene) or a chlorinated hydrocarbon (e.g., chloroform or1,2-dichloroethane) are advantageously added. The esterification takesplace under mild conditions if the water of reaction is bound chemicallyby adding a preferably equimolar amount of a carbodiimide (e.g.,N,N'-dicyclohexylcarbodiimide), wherein inert solvents can be used,e.g., ether, dioxane, benzene or 1,2-dimethoxyethane, and a base, e.g.,pyridine, can be added. The methyl ester (or ethyl ester) can also beproduced by reaction of the free acid, according to processes describedin the literature, with diazomethane (or diazoethane, respective) in aninert solvent, e.g., ether, benzene or methanol. Esters of Formula 1 (Z= OR₁) can also be prepared by chemical addition of the carboxylic acids1 (Z = OH) to olefins (e.g., isobutylene). This chemical addition isaccomplished according to methods described in this literature,preferably in the presence of a catalyst (e.g., ZnCl₂, BF₃, H₂ SO₄,arylsulfonic acids, pyrophosphoric acid, boric acid, oxalic acid), attemperatures of from 0° to 200°, under pressures of from 1 to 300atmospheres, and in an inert solvent, e.g., ether, THF, dioxane,benzene, toluene or xylene.

Esters of Formula 1 (Z = OR₁) can also be produced by the reaction ofmetallic salts of the acids 1 (Z = OH), preferably the alkali metal,lead, or silver salts, with alkyl halogenides corresponding to therespective alcohol, e.g., those of the formula R₁ Hal, optionally in aninert solvent, e.g., ether, benzene or petroleum ether, or with an alkylchlorosulfite, e.g., those of the formula R₁ OSOCl and thermolysis ofthe thus-obtained adducts.

The thus-obtained acids and esters of Formula 1 (Z = OH or OR₁) can beconverted into the corresponding ethanolamides (Formula 1, Z = NHCH₂ CH₂OH) by treatment with amidating agents. Most suitable as the amidatingagent is ethanolamine. The amidation takes place according toconventional methods. The reaction is carried out in the presence orabsence of an additional inert solvent. Suitable solvents are, forexample, hydrocarbons, e.g., benzene, toluene or xylene, halogenatedhydrocarbons, e.g., methylene chloride, chloroform or1,2-dichloroethane, ethers, e.g., diethyl ether, THF or dioxane, amides,e.g., DMF, dimethylacetamide or HMPA. It is also possible to employ anexcess of the ethanolamine as the solvent. The presence of a catalyst ora dehydrating agent can be advantageous. The temperatures during theamidation range suitably from about -20° to 200°. When starting with thefree acids 1 (Z = OH), it is advantageous to conduct the amidation intwo stages, by first converting the free acid into an acid halogenide,for example, into the chloride with thionyl chloride, and then reactingthe product with ethanolamine.

The compounds of Formula 1 can be present in an optionally inactive formor, when they contain a center of asymmetry, also in an optically activeform. Racemates of Formula 1 can be separated into the optical antipodesthereof by means of methods disclosed in the literature. Carboxylicacids of Formula 1 (Z = OH) can be converted, for example, withoptically active amines, e.g., quinine, brucine, or strychnine, intodiastereomeric salts which can be separated by crystallization and splitup by hydrolysis.

A basic compound of Formula 1 (R = 1-methyl-4-piperidyl) can beconverted into an acid addition salt thereof with an acid. Suitable forthis reaction are acids yielding physiologically acceptable salts,including both organic and inorganic acids, e.g., aliphatic, alicyclic,araliphatic, aromatic and heterocyclic, mono- or polybasic carboxylicand sulfonic acids, e.g., formic acid, acetic acid, propionic acid,pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelicacid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,aminocarboxylic acids, sulfamic acid, benzoic acid, salicyclic acid,2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonicacid, naphthalene-mono- and -disulfonic acids, sulfuric acid, nitricacid, hydrohalic acids, e.g., hydrochloric acid and hydrobromic acid,and phosphoric acids, e.g., orthophosphoric acid.

The acidic compounds of Formula 1 (Z = OH) can be converted, by reactionwith a base, into a physiologically acceptable metal or ammonium salt.Especially suitable salts are the sodium, potassium, magnesium, calcium,and ammonium and substituted ammonium salts.

Conversely, compounds of Formula 1 can be liberated from the acidaddition salts thereof by treatment with strong bases and/or from themetal and ammonium salts thereof by treatment with acids.

The compounds of Formula 1 and/or the physiologically acceptable saltsthereof can be employed as medicinal agents in human or veterinarymedicine, in admixture with solid, liquid and/or semiliquid excipients.Suitable vehicles are those organic or inorganic substances suitable forparenteral, enteral, or topical application and which do not react withthe novel compounds, such as, for example, water, vegetable oils, benzylalcohols, polyethylene glycols, gelatin, lactose, amylose, magnesiumstearate, talc, vaseline, cholesterol. Suitable for parenteralapplication are, furthermore, solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. For enteraladministration, suitable are tablets, dragees, capsules, syrups,elixirs, or suppositories, and for topical administration, ointments,creams, or powders. The above-indicated preparations can optionally besterilized or contain auxliary substances, such as lubricants,preservatives, stabilizers, or wetting agents, emulsifiers, salts forinfluencing the osmotic pressure, buffers, coloring, flavoring and/oraromatic substances.

The substances are preferably administered in doses of between 10 and1000 mg. per dosage unit.

In particular, the substances are preferably administered in doses ofbetween 30 and 300 mg. per dosage unit. The daily dose is preferablybetween about 0.2 and 20 mg. per kg. body weight. Oral application ispreferred.

The cholesterol and the triglyceride blood-level-lowering activities canbe demonstrated in the serum of rats according to the methods of Levineet al. (Automation in Analytical Chemistry, Technicon Symposium, 1967,Mediad, N.Y., pp. 25 - 28) and Noble and Campbell (Clin. Chem., vol 16,pp. 166 - 170, 1970), respectively.

The temperatures herein are indicated in degrees Celsius. "Working up asusual" means the following: If necessary, water is added; the mixture isextracted with ethyl acetate, ether, or chloroform; the product isseparated; the organic extract is washed with water, dried over sodiumsulfate, filtered, and evaporated; and the thus-obtained product ispurified by distillation or crystallization.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1

a. 2.3 g. of sodium is dissolved in 100 ml. of absolute ethanol; 20 g.of 4-phenoxymethylphenol and 18.1 g. of the ethyl ester of2-bromopropionic acid are added thereto, and the mixture is refluxed for3 hours and evaporated. After working up the mixture as usual, the ethylester of 2-(4-phenoxymethylphenoxy)-propionic acid is obtained.

Analogously, with the use of the following starting compounds:

4-p-fluorophenoxymethylphenol

4-p-chlorophenoxymethylphenol

4-p-bromophenoxymethylphenol

4-p-iodophenoxymethylphenol

the following final products are obtained with the ethyl ester of2-chloro-, 2-bromo-, or 2-iodopropionic acid:

ethyl ester of 2-(4-p-fluorophenoxymethylphenoxy)-propionic acid

ethyl ester of 2-(4-p-chlorophenoxymethylphenoxy)-propionic acid

ethyl ester of 2-(4-p-bromophenoxymethylphenoxy)-propionic acid

ethyl ester of 2-(4-p-iodophenoxymethylphenoxy)-propionic acid.

Analogously, the products set forth below are produced with the ethylester of 2-chloro-, 2-bromo-, or 2-iodoisobutyric acid:

ethyl ester of 2-(4-phenoxymethylphenoxy)-2-methylpropionic acid

ethyl ester of 2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionicacid, m.p. 54°-55°

ethyl ester of 2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid

ethyl ester of 2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid

ethyl ester of 2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.

b. 7 g. of the ethyl ester of 2-(4-phenoxymethylphenoxy)-propionic acidis refluxed with 7 g. of KOH in 70 ml. of ethanol for 2 hours. Themixture is then evaporated, dissolved in water, washed with ether,acidified, and worked up as usual, thus obtaining2-(4-phenoxymethylphenoxy)-propionic acid.

Analogously, the following products are obtained by the saponificationof the corresponding esters:

2-(4-p-fluorophenoxymethylphenoxy)-propionic acid

2-(4-p-chlorophenoxymethylphenoxy)-propionic acid

2-(4-p-bromophenoxymethylphenoxy)-propionic acid

2-(4-p-iodophenoxymethylphenoxy)-propionic acid

2-(4-phenoxymethylphenoxy)-2-methylpropionic acid, m.p. 122°-124°

2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid, m.p.123°-125°

2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid, m.p.151°-153°

2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid, m.p. 170°-172°

2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.

c. 5 g. of 2-(4-phenoxymethylphenoxy)-propionic acid is dissolved in 200ml. of saturated methanolic hydrochloric acid; the mixture is allowed tostand for 12 hours at room temperature, refluxed for 2 hours, andevaporated. The usual working up operation yields the methyl ester of2-(4-phenoxymethylphenoxy)-propionic acid.

Analogously, the corresponding methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, and/or sec.-butyl esters, for example the ethylester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl esterand/or sec.-butyl ester of 2-(4-phenoxymethylphenoxy)-propionic acid areobtained from the acids set forth under (b) by reaction with HCl inmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, andsec.-butanol, respectively.

d. One gram of 2-(4-phenoxymethylphenoxy)-propionic acid is dissolved in20 ml. of ether and combined dropwise with etherdiazomethane solutionuntil the yellow coloring is permanent. After evaporation, the methylester of 2-(4-phenoxymethylphenoxy)-propionic acid is obtained.

Analogously, the following compounds are produced from the correspondingacids with diazomethane:

the methyl ester of each of the following acids:

2-(4-p-fluorophenoxymethylphenoxy)-propionic acid

2-(4-chlorophenoxymethylphenoxy)-propionic acid

2-(4-p-bromophenoxymethylphenoxy)-propionic acid

2-(4-p-iodophenoxymethylphenoxy)-propionic acid

2-(4-phenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.

e. 2.72 g. of 2-(4-phenoxymethylphenoxy)-propionic acid is dissolved in12 ml. of HMPA and mixed, at 10°, with 0.72 ml. of thionyl chloride.After two hours of agitation at -5°, 1.23 g. of1-methyl-4-hydroxypiperidine is added. The mixture is agitated overnightat 20°, poured on water, and worked up as usual, thus obtaining the(1-methyl-4-piperidyl) ester of 2-(4-phenoxymethylphenoxy)-propionicacid.

Analogously, the (1-methyl-4-piperidyl) esters of each of the followingacids are correspondingly obtained:

2-(4-p-fluorophenoxymethylphenoxy)-propionic acid

2-(4-p-chlorophenoxymethylphenoxy)-propionic acid

2-(4-p-bromophenoxymethylphenoxy)-propionic acid

2-(4-p-iodophenoxymethylphenoxy)-propionic acid

2-(4-phenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid, fumarate,m.p. 134°-135°

2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.

f. 2.72 g. of 2-(4-phenoxymethylphenoxy)-propionic acid is dissolved in12 ml. of HMPA. At -10°, 0.77 ml. of thionyl chloride is added thereto,and the mixture is agitated for 2 hours at -5°. Thereafter, 2.5 ml. ofethanolamine is added and the reaction mixture is stirred overnight at20°. The mixture is then poured on ice and worked up as usual, yieldingthe 2-hydroxyethylamide of 2-(4-phenoxymethylphenoxy)-propionic acid.

Analogously, the 2-hydroxyethyl amides of each of the following acidsare correspondingly obtained:

2-(4-p-fluorophenoxymethylphenoxy)-propionic acid

2-(4-p-chlorophenoxymethylphenoxy)-propionic acid

2-(4p-bromophenoxymethylphenoxy)-propionic acid

2-(4-p-iodophenoxymethylphenoxy)-propionic acid

2-(4-phenoxymethylphenoxy)-2-methyl-propionic acid

2-(4-p-flurophenoxymethylphenoxy)-2methylpropionic acid

2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid, m.p. of the2-hydroxyethylamide: 110°-112°

2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid

2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.

EXAMPLE 2

A mixture of 20 g. of 4-phenoxymethylphenol and 13.2 g. of the ethylester of 2-hydroxyisobutyric acid is combined with 15 g. of sulfuricacid, and the reaction mixture is agitated for 2 hours at 50°-60°. Aftercooling, the mixture is combined with water and worked up as usual,obtaining the ethyl ester of2-(4-phenoxymethylphenoxy)-2methyl-propionic acid.

EXAMPLE 3

20 g. of 4-phenoxymethylphenol is dissolved in 200 ml. of acetone. Underagitation, 4 g. of NaOH is added dropwise to the reaction mixture, andthen, under stirring and boiling, 16.7 g. of 2-bromoisobutyric acid isadded dropwise thereto (or 12.25 g. of 2-chloroisobutyric acid is usedinstead) in 60 ml. of acetone. The mixture is agitated for 1 hour at 56°and allowed to stand for 24 hours. The acetone is distilled off, and theresidue is worked up as usual, thus producing2-(4-phenoxymethylphenoxy)-2-methylpropionic acid.

EXAMPLE 4

At 40°-50°, 30 g. of chloroform is added dropwise to a mixture of 20 g.of 2-phenoxymethylphenol, 100 ml. of acetone, and 21 g. of pulverizedpotassium hydroxide. The mixture is refluxed for 12 hours, evaporated,mixed with water, and worked up as usual, thus obtaining2-(4-phenoxymethylphenoxy)-2-methylpropionic acid.

EXAMPLE 5

2.3 g. of sodium is dissolved in 250 ml. of absolute ethanol; 9.4 g. ofphenol and 28.6 g. of the ethyl ester of2-(p-bromomethylphenoxy)-propionic acid [obtainable by reactingp-hydroxybenzyl alcohol with ethyl 2-bromopropionate to the ethyl esterof 2-(p-hydroxymethylphenoxy)-propionic acid and subsequent reactionwith SOBr₂ ] are added thereto, and the mixture is refluxed for 3 hoursand evaporated. The usual working-up procedure yields the ethyl ester of2-(4-phenoxymethylphenoxy)-propionic acid.

Analogously, the ethyl ester of2-(4-phenoxymethylphenoxy)-2-methylpropionic acid is obtained from theethyl ester of 2-p-bromomethylphenoxyisobutyric acid (obtainable bybromination of the ethyl ester of 2-p-methylphenoxyisobutyric acid withN-bromosuccinimide);

and the remaining esters set forth in Example 1(a) are produced withp-fluorophenol, p-chlorophenol, p-bromophenol, and p-iodophenol,respectively.

EXAMPLE 6

One gram of 2-(4-phenoxymethylphenoxy)-propionitrile (obtainable from4-phenoxymethylphenol and 2-bromopropionitrile) is refluxed in 15 ml. ofethanol and 2 ml. of water with 2 g. of KOH for 40 hours. The mixture isthen evaporated and worked up as usual, yielding2-(4-phenoxymethylphenoxy)-propionic acid.

EXAMPLE 7

One gram of 2-(4-phenoxymethylphenoxy)-propionitrile is refluxed for 2hours with 6 ml. of acetic acid and 6 ml. of concentrated hydrochloricacid. The mixture is evaporated, the residue dissolved in dilute sodiumhydroxide solution, washed with ether, and worked up as usual, thusobtaining 2-(4-phenoxymethylphenoxy)-propionic acid.

EXAMPLE 8

The iminoethyl ether hydrochloride of2-(4-phenoxymethylphenoxy)-propionic acid [obtainable from2-(4-phenoxymethylphenoxy)-propionitrile and ethanol/HCl in ether at 0°]is refluxed for one hour with 25 ml. of water. After the mixture hasbeen worked up as usual, the ethyl ester of2-(4-phenoxymethylphenoxy)-propionic acid is produced.

EXAMPLE 9

One gram of 2-(4-phenoxymethylphenoxy)-propionamide (obtainable from thenitrile with sulfuric acid at 25°) and 2 g. of KOH are refluxed in 40ml. of ethanol for 3 hours; after evaporation, the mixture is worked upas usual, yielding 2-(4-phenoxymethylphenoxy)-propionic acid.

EXAMPLE 10

A mixture of 1 g. of 2-(4-phenoxymethylphenoxy)-propionamide, 2 ml. ofconcentrated hydrochlorid acid, and 2 ml. of acetic acid is refluxed for48 hours and, after adding water, worked up as usual, yielding2-(4-phenoxymethylphenoxy)-propionic acid.

The following examples relate to pharmaceutical preparations containingphenoxypropionic acid derivatives of general Formula 1:

EXAMPLE A: Tablets

A mixture consisting of

300 kg. of 2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid,

500 kg. of lactose,

160 kg. of corn starch,

20 kg. of cellulose powder, and

20 kg. of magnesium stearate

is compressed to tablets in the usual manner so that each tabletcontains 300 mg. of the active agent.

EXAMPLE B: Dragees

Tablets are compressed in accordance with Example A and then coated inthe usual manner with a layer of sugar, corn starch, talc, andtragacanth.

Analogously, tablets and dragees are obtainable which contain one ormore of the remaining effective agents of Formula 1 and/or thephysiologically acceptable salts thereof.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A phenoxypropionic acid derivative of the formula ##SPC8##wherein Q is H or halogen, R is H or CH₃, Z is --OH or --OR₁ , and R₁ is alkyl of 1-4 carbon atoms or 1-methyl-4-piperidyl, and the physiologically acceptable salts thereof.
 2. A compound of claim 1 wherein Z is --OH, methoxy, ethoxy or 1-methyl-4-piperidyloxy.
 3. A compound of claim 1 wherein Q is H or Cl.
 4. A compound of claim 1, 2-(4-phenoxymethylphenoxy)-propionic acid.
 5. A compound of claim 1, ethyl ester of 2-(4-phenoxymethylphenoxy)-propionic acid.
 6. A compound of claim 1, 2-(4-p-fluorophenoxymethylphenoxy)-propionic acid.
 7. A compound of claim 1, ethyl ester of 2-(4-p-fluorophenoxymethylphenoxy)-propionic acid.
 8. A compound of claim 1, 2-(4-p-chlorophenoxymethylphenoxy)-propionic acid.
 9. A compound of claim 1, ethyl ester of 2-(4-p-chlorophenoxymethylphenoxy)-propionic acid.
 10. A compound of claim 1, 2-(4-phenoxymethylphenoxy)-2-methylpropionic acid.
 11. A compound of claim 1, ethyl ester of 2-(4-phenoxymethylphenoxy)-2-methylpropionic acid.
 12. A compound of claim 1, 2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid.
 13. A compound of claim 1, ethyl ester of 2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid.
 14. A compound of claim 1, (1-methyl-4-piperidyl) ester of 2-(4-p-fluorophenoxymethylphenoxy)-2-methylpropionic acid.
 15. A compound of claim 1, 2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid.
 16. A compound of claim 1, ethyl ester of 2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid.
 17. A compound of claim 1, (1-methyl-4-piperidyl) ester of 2-(4-p-chlorophenoxymethylphenoxy)-2-methylpropionic acid.
 18. A compound of claim 1, 2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid.
 19. A compound of claim 1, ethyl ester of 2-(4-p-bromophenoxymethylphenoxy)-2-methylpropionic acid.
 20. A compound of claim 1, 2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.
 21. A compound of claim 1, ethyl ester of 2-(4-p-iodophenoxymethylphenoxy)-2-methylpropionic acid.
 22. A compound of claim 1 wherein Z is OH.
 23. A compound of claim 1 wherein Z is methoxy or ethoxy. 